Biochemical abnormalities underlying calcium pyrophosphate dihydrate (CPPD) deposition disease will be studied to determine its pathogenesis and allow logical formulation of preventive or therapeutic approaches to the associated degenerative and inflammatory arthritides. Inorganic pyrophosphate (PPi), which accumulates as CPPD crystals, will be analyzed in intra- and extra-cellular compartments; and enzymes capable of influencing its synthesis or degradation will be studied. PPi will be measured in fibroblasts cultured from skin biopsies of patients with familial, sporadic and metabolic disease-associated CPPD deposition and normals. Variables affecting intracellular PPi levels will be isolated. Ectoenzymes, 5'nucleotidase and nucleotide pyrophosphohydrolase, which may be important in PPi generation, will be characterized in canine articular cartilage organ culture, and analyzed in human specimens of normal and diseased cartilage. A newly identified magnesium-dependent, calcium-inhibitible ecto-pyrophosphatase, which is of potential significance in extracellular PPi metabolism, will be evaluated in cartilage organ culture, isolated, and characterized. Ecto-pyrophosphatase will be measured in normal and pathological human cartilage. The cooperative effect of these ectoenzymes will be examined by measuring the effect upon PPi elaboration of the addition of specific inhibitors of each enzyme. Canine articular cartilage will be incubated with the substrates for PPi formation and inhibitors of PPi degradation to optimize conditions for CPPD crystal formation, in an attempt to develop an in vitro model of CPPD disease.